Core A - Variant prioritization and curation core

项目摘要--核心A 离子通道基因的变异代表了严重儿科癫痫最常见的遗传发现。 然而，对与经络病相关的癫痫的遗传图谱的了解是不完整的，因为 变体发现的快速步伐和变体解释的挑战。此外，现有的许多 相关知识并不广泛，包括最近发现的变种，相关的临床 表型，变异功能分析的协议，以及整合功能、遗传和 临床资料以评估致病性和预后。不同的优先级排序和配置核心(核心A)将 修改和部署现有的协作性生物信息学和变种管理平台，以支持特派团 我们中心的。核心A将作为正在进行的NIH管理工作的接口，包括ClinVar和Clingen， 确保中心生成的功能数据是持久的和完全可访问的。 在目标1中，我们将对癫痫相关电压门控离子通道基因的变异进行分类。最大限度地提高 在项目1-3中进行的体外和体内功能研究的效用，核心A将建立和维持 电压门控离子通道基因中已知癫痫相关变异的数据库。我们将组装基因 以及来自不同来源的表型信息，包括出版物、特定于基因座的数据库，以前 来自诊断实验室(约30,000名患者)和研究研究(约20,000名受试者)的未披露数据。在……里面 目的2，我们将优先考虑离子通道基因的变异以进行功能评估。的离子通道基因变异体 建议的高通量研究将选择最高的临床重要性和分析有效性 项目1.为了确定哪些变体符合该标准，我们将应用一系列标准，包括已建立的 美国医学遗传学和基因组学(ACMG)诊断规则和先进的数据驱动 该算法考虑了突变的“热点”、基因家族信息和区域不容忍。基于 根据适用的标准，我们将在5年的资助期内优先考虑1,000种变种进行功能评估。在AIM 3、我们将使用功能数据反复改进不同的分类和诊断标准。我们会申请 来自中心的结果，为变体和Clingen内的工作提出改进的分类规则 该联盟将开发一种基于基因/变异的早发性癫痫分类学，与 国际抗癫痫联盟(ILAE)分类和术语。为确保公众访问，核心A 成员将扩大与NIH资助的Clingen财团和ClinVar的持续合作 通过将所有机密离子通道变体和关键支持证据作为专家提交给ClinVar进行归档 面板。作为这项工作的一部分，我们将扩充现有的ClinVar数据元素，以包括Variant上的数据字段 使用由项目1开发的本体来实现功能。

PROJECT SUMMARY – CORE A Variants in ion channel genes represent the most common genetic finding in severe pediatric epilepsies. However, knowledge of the genetic landscape of channelopathy-associated epilepsy is incomplete, owing to the rapid pace of variant discovery and the challenges of variant interpretation. Further, much of the existing relevant knowledge is not widely available, including recently identified variants, associated clinical phenotypes, protocols for variant functional analysis, and best practices for integrating functional, genetic, and clinical data to assess pathogenicity and prognosis. The Variant Prioritization and Curation Core (Core A) will modify and deploy an existing collaborative bioinformatics and variant curation platform to support the mission of our Center. Core A will serve as an interface to ongoing NIH curation efforts, including ClinVar and ClinGen, to ensure that functional data generated by the Center are enduring and fully accessible. In Aim 1, we will catalog variants in the epilepsy-associated voltage-gated ion channel genes. To maximize the utility of in vitro and in vivo functional studies performed in Projects 1-3, Core A will establish and maintain a database of known epilepsy-associated variants in voltage-gated ion channel genes. We will assemble genetic and phenotypic information from diverse sources including publications, locus-specific databases, previously undisclosed data from diagnostic laboratories (~30,000 patients) and research studies (~20,000 subjects). In Aim 2, we will prioritize variants in ion channel genes for functional evaluation. Ion channel gene variants of the highest clinical importance and analytical validity will be selected for the high-throughput studies proposed in Project 1. To identify which variants meet this standard, we will apply a range of criteria including established American College of Medical Genetics and Genomics (ACMG) diagnostic rules and an advanced data-driven algorithm that considers mutational ‘hot spots,’ gene family information, and regional intolerance. Based on the applied criteria, we will prioritize 1,000 variants for functional evaluation over the 5-year funding period. In Aim 3, we will use functional data to iteratively refine variant classifications and diagnostic criteria. We will apply results from the Center to propose improved classification rules for variants and work within the ClinGen consortium to develop a gene/variant-based taxonomy of early onset epilepsy that harmonizes with the International League Against Epilepsy (ILAE) classification and terminology. To ensure public access, Core A members will expand their ongoing collaboration with the NIH-funded ClinGen consortium, and the ClinVar archive by submitting all classified ion channel variants and key supporting evidence to ClinVar as an Expert Panel. As part of this effort, we will augment existing ClinVar data elements to include data fields on variant function using an ontology developed by Project 1.